MUC13 Mucin in Colerectal Cancer Health Disparity

MUC13 粘蛋白在结肠直肠癌健康差异中的作用

• 批准号: 10016192
• 负责人: Subhash C. Chauhan
• 金额: $ 33.99万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016192
• 关键词: 3' Untranslated Regions; Adenomatous Polyps; Affect; African American; American Indians; Applications Grants; Benign; Binding; Caucasians; Cell Line; Cell Nucleus; Cell Survival; Cell membrane; Cells; Colorectal Cancer; Cytoplasm; Data; Diagnosis; Disease; Disease Progression; ERBB2 gene; Early Diagnosis; Etiology; Expression Profiling; Functional disorder; Genetic Polymorphism; IL6 gene; Individual; Inflammation Mediators; Interleukin-6; Intrinsic factor; Investigation; JAK2 gene; Laboratories; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mucins; Neoplasm Metastasis; Neoplastic Polyp; Nuclear; Outcome Study; Oxidative Stress; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Phosphorylation; Population; Predisposition; Prevalence; Preventive; Proteins; Publishing; RNA Splicing; Regulation; Research; Risk stratification; Role; SHH gene; STAT5B gene; Sampling; Signal Pathway; Signal Transduction Pathway; Single Nucleotide Polymorphism; Stat5 protein; TP53 gene; Testing; Therapeutic; Tissue Sample; Tissues; Underserved Population; Validation; Variant; base; biomarker identification; cancer cell; cancer health disparity; caucasian American; cell growth; clinically relevant; clinically significant; cohort; colon cancer cell line; colorectal cancer progression; cytokine; design; differential expression; experience; health disparity; improved; innovation; insight; metastatic colorectal; mortality; next generation; novel; novel marker; outcome forecast; overexpression; public health relevance; response; transcription factor; transcriptome sequencing; treatment planning; tumor microenvironment

 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second most lethal malignancy in the USA and affects over a million people every year. A significant CRC health disparity exists between African Americans (AA), American Indians (AI) and Caucasians (CA) in relation to its occurrence, drug response and mortality. Due to this, the overall mortality is highr among AA/AI compared to CA. However, the underlying molecular mechanisms of this disparity in AA/AI are not known. Therefore, it is highly imperative to understand the molecular basis and the identification of biomarker(s) that can be used for early stage diagnosis, metastasis and drug response to reduce this unacceptable health disparity. Our laboratory has identified a novel transmembrane mucin, MUC13, which is highly overexpressed/aberrantly localized in CRC and is involved in its pathogenesis. Additionally, our recent preliminary data suggest a markedly higher and aberrant expression of MUC13 in AA/AI CRC samples compared to CA counter parts. We have shown that MUC13 is an important modulator of several signal-transduction pathways and affects multiple key proteins involved in cell growth and survival, such as sonic hedgehog, HER2 and p53. Our published and preliminary studies have suggested an aberrant expression of MUC13 which has implications in CRC progression and metastasis. Based on these compelling evidence, we hypothesize that the differential/aberrant expression of MUC13 and/or MUC13 variants are underlying factors associated with CRC health disparity. In addition, we hypothesize this differential MUC13 expression is regulated by certain microRNAs (miR-145 and miR-132) and inflammatory mediators produced by the tumor microenvironment (e.g. interleukin-6 mediated STAT5B phosphorylation) resulting in malignant colorectal cancer cells phenotypes among AA/AI populations. Three specific aims with comprehensive experimental approach are proposed to test this hypothesis. In Aim 1, we propose to study the expression profile of MUC13 in Caucasians, African Americans and American Indians CRC tissues and its correlation with disease progression, metastasis and patient survival. Aim 2 will investigate the presence of MUC13 spliced variants/single nucleotide polymorphisms (SNPs) and their association with chemoresistance, metastasis and CRC health disparity. Aim 3 intends to elucidate the molecular mechanisms of MUC13 regulation in clinically relevant CRC tissues and cell line models. We will also investigate how various intrinsic factors can induce aberrant/ altered subcellular localization of MUC13, in clinically relevant CRC cell line models, as aberrant subcellular localization (cytoplasmic, nuclear) of MUC13 has also been associated with disease stage, prognosis and metastasis. The results of this multi factorial study will determine if MUC13 can be used as a molecular signature for early detection of aggressive and metastatic CRC in AA and AI. This comprehensive study will further provide important insights regarding MUC13 etiology in CRC and help in designing preventive and therapeutic strategies to reduce CRC mortality and CRC health disparity in underserved populations.

 描述（由申请人提供）：结直肠癌 (CRC) 是美国第二大致命恶性肿瘤，每年影响超过一百万人，非裔美国人 (AA)、美洲印第安人 (AI) 和白种人之间存在显着的结直肠癌健康差异。 (CA) 与它的发生、药物反应和死亡率有关。因此，与 CA 相比，AA/AI 的总体死亡率较高。然而，AA/AI 中这种差异的潜在分子机制尚不清楚。因此，非常有必要了解可用于早期诊断、转移和药物反应的生物标记物的分子基础和鉴定，以减少这种不可接受的健康差异。 MUC13 在 CRC 中高度过度表达/异常定位，并参与其发病机制。此外，我们最近的初步数据表明，与 AA/AI CRC 样本相比，MUC13 的表达明显较高且异常。我们已经证明，MUC13 是多种信号转导途径的重要调节剂，并影响细胞生长和存活的多种关键蛋白，例如 sonic hedgehog、HER2 和 p53。我们已发表的研究和初步研究表明其存在异常表达。 MUC13 的表达对 CRC 进展和转移有影响 基于这些令人信服的证据，我们认为 MUC13 和/或 MUC13 变体的差异/异常表达是与 CRC 健康相关的潜在因素。此外，我们发现这种差异性 MUC13 表达受到某些 microRNA（miR-145 和 miR-132）和肿瘤微环境产生的炎症介质（例如白细胞介素 6 介导的 STAT5B 磷酸化）的调节，从而导致恶性结直肠癌细胞表型。 AA/AI 群体。提出了三个具体目标和综合实验方法来检验这一假设。在目标 1 中，我们建议研究 AA/AI 的表达谱。白种人、非裔美国人和美洲印第安人 CRC 组织中的 MUC13 及其与疾病进展、转移和患者生存的相关性目标 2 将研究 MUC13 剪接变体/单核苷酸多态性 (SNP) 的存在及其与化疗耐药、转移和患者生存的关系。 CRC 健康差异。目标 3 旨在阐明临床相关 CRC 组织和细胞系模型中 MUC13 调节的分子机制。还将研究在临床相关的 CRC 细胞系模型中，各种内在因素如何诱导 MUC13 的异常/改变的亚细胞定位，如异常 MUC13 的亚细胞定位（细胞质、细胞核）也与疾病分期、预后和转移相关。这项多因素研究的结果将确定 MUC13 是否可以用作早期检测 AA 和转移性 CRC 的分子特征。 AI。这项综合研究将进一步提供有关 CRC 中 MUC13 病因学的重要见解，并有助于设计预防和治疗策略，以降低服务不足人群的 CRC 死亡率和健康差异。

项目成果

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Magnetic nanoformulations for prostate cancer.

• DOI: 10.1016/j.drudis.2017.04.018
• 发表时间: 2017-08
• 期刊: Drug discovery today
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Tannic acid-inspired paclitaxel nanoparticles for enhanced anticancer effects in breast cancer cells.

• DOI: 10.1016/j.jcis.2018.09.072
• 发表时间: 2019-02-01
• 期刊: Journal of colloid and interface science
• 影响因子: 9.9
• 作者: Chowdhury P;Nagesh PKB;Hatami E;Wagh S;Dan N;Tripathi MK;Khan S;Hafeez BB;Meibohm B;Chauhan SC;Jaggi M;Yallapu MM
• 通讯作者: Yallapu MM

Optical detection of the structural properties of tumor tissue generated by xenografting of drug-sensitive and drug-resistant cancer cells using partial wave spectroscopy (PWS).

• DOI: 10.1364/boe.10.006422
• 发表时间: 2019-08
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: P. Adhikari;P. K. Nagesh;Fatemah Alharthi;S. Chauhan;M. Jaggi;M. Yallapu;P. Pradhan

MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway.

• DOI: 10.26508/lsa.202301975
• 发表时间: 2023-12
• 期刊: Life science alliance
• 影响因子: 4.4